Diastereomeric 5R,6S-6-(1R-hydroxyethyl)-2-(cis-1-oxo-3-thiolanylthio)-2-penem-3-carboxylic acids

ABSTRACT

Diastereomeric 5R,6S-6-(1R-hydroxyethyl)-2-(1S-oxo-3R-thiolanylthio)-2-penem-3-carboxylic acid and 5R,6S-6-(1R-hydroxyethyl)-2-(1R-oxo-3S-thiolanylthio )-2-penem-3-carboxylic acid, and pharmaceutically-acceptable salts and in vivo hydrolyzable esters thereof, useful as systemic antibacterial agents; and intermediates and processes which are useful in the said synthesis of said diastereoisomers.

BACKGROUND OF THE INVENTION

The present invention is directed to antibacterial compounds which arediastereomeric5R,6S-6-(1R-hydroxyethyl)-2-(cis-1-oxo-3-thiolanylthio)-2-penem-3-carboxylicacids, viz., the 2-(1S-oxo-3R-thiolanylthio) variant of the formula (I)below, and the 2-(1R-oxo-3S-thiolanylthio) variant of the formula (II)below; the pharmaceutically-acceptable salts and in vivo hydrolyzableesters thereof; and intermediates and processes useful in thepreparation of said diastereoisomers.

Antibacterial5R,6S-6-(1R-hydroxyethyl)-2-(cis-1-oxo-3-thiolanylthio)-2-penem-3-carboxylicacid, which is a diastereomeric mixture of two compounds, was earlierdisclosed as a valuable antibacterial substance by Hamanaka, U.S. Pat.No. 4,619,924 and European patent application No. 130,025. Althoughdetectable by analytical methods, the pure diastereomeric compounds ofassigned structure have heretofore been unavailable. Disclosure of animproved process for that diastereomeric mixture from racemiccis-3-(acetylthio)thiolane 1-oxide, which employs mixed diastereomericintermediates otherwise analogous to those presently used, will be foundin a European patent application by Volkmann et al., scheduled forpublication on May 27, 1987 under the No. 223,397.

Concerning the present optically active precursors, Brown et al., J. Am.Chem. Soc., vol. 108, pp. 2049-2054 (1986) have reported the synthesisof (S)-3-hydroxythiolane [inadvertently depicted as the (R)-isomer, butactually of configuration opposite to that of the present(R)-3-hydroxythiolane, of the formula (XI) below]by asymmetrichydroboration of 2,3-dihydrothiophene. Partial enzymic oxidation ofracemic 3-hydroxythiolane by Jones et al., Can. J. Chem., vol. 59, pp.1574-1579 (1981) permitted recovery of 3-hydroxythiolane containing the(R)-isomer in slight excess. Present optically active precursors(R)-(2-methanesulfonyloxyethyl)oxirane [of the formula (XIII) belowwherein R⁹ =CH₃ ] and (S)-2-bromo-1,4-di(methanesulfonyloxy)butane [ofthe formula (Xa) below wherein R⁸ =CH₃ ] are known compounds; bothpreparable according to Shibata et al., Heterocycles, vol. 24, pp.1331-1346 (1986); the former also according to Boger et al., J. Org.Chem., vol. 46, pp. 1208-1210 (1981).

SUMMARY OF THE INVENTION

We have now discovered methods for preparing the diastereomeric penemcompounds, 5R,6S-6-(1R-hydroxy-ethyl)-2-(1S-oxo-3R-thiolanylthio)-3-carboxylates, ofthe absolute stereochemical formula ##STR1## and 5R,6S-6-(1R-hydroxyethyl)-2-(1R-oxo-3S-thiolanyl-thio)-3-carboxylates, ofthe absolute stereochemical formula ##STR2## wherein R is hydrogen or aradical forming an ester hydrolyzable under physiological conditions;and the pharmaceutically-acceptable cationic salt thereof when R ishydrogen.

Because each of these compounds, and their several immediate precursors,are single, homogeneous compounds, the quality of the final products ismuch better controlled relative to the previously reporteddiastereomeric mixture of these compounds, an important factor inclinical use. Based on in vitro studies of the presently isolatedcompounds (I) and (II), both show about the same intrinsic antibacterialactivity. However, it is surprising that, in the form of theirpivaloyloxymethyl esters, the isomer of the formula (II) is betterabsorbed orally than the isomer (I); and, evidently as a result of alowered level of metabolic destruction, the isomer (II) shows virtuallytwice the urine recovery as the isomer (I) whether administeredparenterally as the sodium salt or orally as the pivaloyloxymethylester. For these reasons, the present pure diastereoisomers arepreferred over the earlier diastereomeric mixture, and the isomers ofthe formula (II) are most preferred.

Said pharmaceutically-acceptable cationic salts include, but are notlimited to, those of sodium, potassium, calcium,N,N'-dibenzylethylenediamine, N-methylglucamine (meglumine) anddiethanolamine. The preferred cationic salts are those of potassium andsodium.

The reference to esters which are hydrolyzable under physiologicalconditions refers to those esters frequently referred to as "pro-drugs."Such esters are now as well-known and common in the penicillin art aspharmaceutically-acceptable salts. Such esters are generally used toenhance oral absorption, but in any event are readily hydrolyzed in vivoto the parent acid. The more preferred ester forming radicals are thosewherein R is:

(5-methyl-1,3-dioxol-2-on-4-yl)methyl;

1H-isobenzofuran-3-on-1-yl;

gamma-butyrolacton-4-yl;

--CHR¹ OCOR² ; or

--CHR¹ OCOOR³ ;

wherein R¹ is hydrogen or methyl: R² is (C₁ -C₆)alkyl, (C₁-C₆)carboxyalkyl, carboxycyclohexyl or carboxyphenyl; and R³ is (C₁-C₆)alkyl. The most preferred radicals are pivaloyloxymethyl and1-(ethoxycarbonyloxy)ethyl.

The present invention is also directed to intermediate compounds of theabsolute stereochemical formulas ##STR3## and ##STR4## wherein R⁴ ishydrogen or a conventional silyl hydroxy protecting group, preferablyt-butyldimethylsilyl; R⁵ is hydrogen, --CH₂ --CX═CH₂, or --CH₂--O--CO--C(CH₃)₃ (with the proviso that R⁵ is --CH₂ --CX═CH₂ when R⁴ ishydrogen); and X is hydrogen or chloro, preferably chloro; or a saltthereof when R⁵ is hydrogen; ##STR5## and ##STR6## wherein R⁶ is saidconventional silyl protecting group; R⁷ is hydrogen or ##STR7## and##STR8## wherein R¹⁰ is --CH₂ --CX═CH₂ or --CH₂ --O--CO--C(CH₃)₃, X ishydrogen or chloro, Y is CH₃ CO, M.sup.⊕, or M.sup.⊕ ##STR9## andM.sup.⊕ is an alkali metal cation, preferably Na.sup.⊕ ; and ##STR10##and ##STR11## wherein R⁸ is (C₁ -C₃) alkyl, phenyl or tolyl, preferablythe latter, and n is 0 or 1.

The present invention is further directed to:

(1) a process for the preparation of a compound of the absolutestereochemical formula ##STR12## wherein M.sup.⊕ is an alkali metalcation, preferably Na.sup.⊕, which comprises the steps of:

(a) conventional cyclization of a compound of the absolutestereochemical formula ##STR13## wherein R⁸ is (C₁ -C₃)alkyl, phenyl orp-tolyl (preferably methyl) with an alkali metal sulfide in areaction-inert solvent to form a compound of the absolute stereochemicalformula ##STR14##

(b) conventional oxidation of the compound of the formula (IXa) withsubstantially one equivalent of oxidant in a reaction-inert solvent toform a compound of the absolute stereochemical formula ##STR15##

(c) conventional nucleophilic displacement of bromo in the compound ofthe formula (IXb) with an alkali metal thioacetate in a reaction-inertsolvent to form a compound of the absolute stereochemical formula##STR16## and (d) conventional conversion of the compound of the formula(VIIb), by the action of the CS₂ and an alkali metal (C₁ -C₃)alkoxide,preferably sodium ethoxide, in a reaction-inert solvent, to form saidcompound of the formula (VIIa);

(2) a process for the preparation of a compound of the absolutestereochemical formula ##STR17## wherein M.sup.⊕ is an alkali metalcation, preferably Na.sup.⊕, which comprises the steps of:

(a) conversion of an epoxide of the absolute stereochemical formula##STR18## wherein R⁹ is (C₁ -C₃)alkyl, phenyl or p-tolyl, preferablymethyl, by the action of an alkali metal sulfide in a reaction-inertsolvent to form a compound of the absolute stereochemical formula##STR19##

(b) conventional sulfonylation of the compound of the formula (XI) in areaction-inert solvent to form a compound of the absolute stereochemicalformula ##STR20## wherein R⁸ is (C₁ -C₃)alkyl, phenyl or tolyl,preferably the latter;

(c) conventional oxidation of the compound of the formula (Xa) in areaction-inert solvent to form a compound of the absolute stereochemicalformula ##STR21##

(d) conventional nucleophilic displacement of R⁸ --SO₂ --O in thecompound of the formula (Xb) with an alkali metal thioacetate in areaction-inert solvent to form a compound of the absolute stereochemicalformula ##STR22## and (e) conventional conversion of the compound of theformula (VIIIb), by the action of CS₂ and an alkali metal alkoxide,preferably sodium ethoxide, in a reaction-inert solvent, to form saidcompound of the formula (VIIIa); and

(3) an improved process for the preparation of a compound of theabsolute stereochemical formula ##STR23## wherein R⁹ is (C₁ -C₃)alkyl,phenyl or p-tolyl, preferably methyl, which comprises the steps of

(a) reacting a compound of the absolute stereochemical formula ##STR24##with Cs₂ CO₃ in a reaction-inert solvent to form a compound of theabsolute stereochemical formula ##STR25## in greater than 90%stoichiometric step yield; and

(b) sulfonylation of the compound of the formula (XV) with a sulfonylchloride of the formula

    R.sup.9 --SO.sub.2 --Cl

in the presence of a tertiary amine in a reaction-inert solvent to formsaid compound of the formula (XIII) in greater than 90% yield.

As used herein, the expression "reaction-inert solvent" refers to asolvent which does not interact with starting materials, reagents,intermediates or products in a manner which adversely affects the yieldof the desired product.

DETAILED DESCRIPTION OF THE INVENTION

The individual diastereomeric compounds of the present invention are nowreadily prepared. An important feature of the present invention is thepreparation of the optically active precursors of the above formulas(VII) and (VIII) from the known optically active compounds of theformulas (XII) and (XIII), respectively.

To prepare the compound (VIIa), the compound of the formula (XII) [knownwhen R⁸ =methyl; prepared analogously when R⁸ is other than methyl] isfirst reacted with an alkali metal sulfide (suitably Na₂ S 9H₂ O), toform (S)-3-bromothiolane (IXa). At least one molar equivalent, usually aslight (e.g., 5-10%) excess of the sulfide salt is used, together withreaction-inert solvent, suitably an aqueous solvent such as an aqueous(C₁ -C₃)alkanol (e.g., aqueous methanol) or aqueous acetonitrile.Temperature is not critical, e.g., 0°-60° C. being generallysatisfactory. Ambient temperatures, e.g., 17°-28° C., are particularlyconvenient, avoiding the cost of heating and cooling, although moreelevated temperatures have the advantage of reducing the time necessaryto complete the reaction.

The intermediate bromothiolane (IXa) is then conventionally oxidized tothe S-oxide (IXb), using substantially one molar equivalent of oxidant(usually in slight excess to achieve complete mono-oxidation, withoutsignificant oxidation to the dioxide). Suitable oxidants arem-chloroperbenzqic acid and potassium peroxymonosulfate[KHSO₅.(KHSO₄)_(1/2). (K₂ SO₄)_(1/2) ]. The oxidation is carried out ina reaction-inert solvent, CH₂ Cl₂ being particularly well-suited for theperbenzoic acid, and acetone for the peroxymonosulfate. Temperature isnot critical, e.g., temperatures of -10° to 40° C. being generallysatisfactory. It is convenient to combine the reagents at reducedtemperature, e.g., 0°-5° C., then allow the reaction to proceed tocompletion at ambient temperature as defined above.

The intermediate sulfoxide (IXb) is then reacted with an alkali metalthioacetate under conventional nucleophilic displacement conditions toform 3R-(acetylthio)thiolane 1S-oxide (VIIb). Usually an excess (e.g.,1.5-2 molar equivalents) of the thioacetate salt is employed in areaction-inert solvent which will permit appreciable concentrations ofboth reactants in order to drive this bimolecular reaction to completionwithin a reasonable period of time. In the present case, acetone is aparticularly well suited solvent. Temperature is not critical, e.g.,30°-100° C. being generally satisfactory, the reflux temperature ofsolvent acetone being eminently satisfactory.

Finally, the acetylthiolane (VIIb) is converted, via the mercaptide salt(VII, Y=M.sup.⊕, to the trithiocarbonate salt (VIIa). The intermediatemercaptide salt is generally formed in situ by the action of an alkalimetal alkoxide, usually in the corresponding alkanol as thereaction-inert solvent, sodium methoxide/methanol, sodiumethoxide/ethanol and sodium isopropoxide/isopropanol all being wellsuited for the purpose, usually at reduced temperature, e.g., -15° to15° C., conveniently near 0° C. Once formed, the mercaptide salt isusually reacted without isolation with at least one molar equivalent ofcarbon disulfide (usually in excess, e.g., 3-5 molar equivalents),usually at even lower temperature, e.g., -40° to 0° C., to form thedesired 3R-(thio(thiocarbonyl)thio)thiolane 1S-oxide of the formula(VIIa). The latter is isolated by conventional methods or alternativelyused in situ in the next process step.

To prepare the compound (VIIIa) the epoxide of the formula (XIII) [knownwhen R⁸ =methyl; in any event prepared according to the improved methoddisclosed elsewhere herein] is first reacted with an alkali metalsulfide, under conditions as disclosed above for the conversion of (XII)to (IXa), in this case forming (R)-3-hydroxythiolane of the formula(XI). The latter is converted to the alkane-, benzene- orp-toluene-sulfonate of the formula (Xa) under conventional conditions,e.g., using substantially one molar equivalent of the correspondingsulfonyl chloride, R⁸ SO₂ Cl, in the presence of at least one molarequivalent of a tertiary amine, preferably p-dimethylaminopyridine, in areaction-inert solvent such as methylene chloride in a non-criticaltemperature range of 0°-50° C., suitably at ambient temperature asdefined above. The compound (Xa) is then oxidized to the sulfoxide (Xb),the sulfonate group nucleophilically displaced with thioacetate to form3S-(acetylthiothiolane 1R-oxide, of the formula (VIIIb), hydrolyzed tothe mercaptide (VIII, Y=M.sup.⊕) and finally reacted with CS₂ to formthe trithiocarbonate (VIIIa), all under the conditions noted above forthe corresponding stepwise conversion of (IXa) to (VIIa).

The present improved two-step process for precursor(R)-(2-methanesulfonyloxyethyl)oxirane of the above formula (XIII)employs (Cs₂ CO₃ in a reaction-inert solvent (e.g., CH₂ Cl₂) at ambienttemperature [in place of the refluxing aqueous NaOH of Shibata et al.,cited above], thus producing, after conventional sulfonylation, saidcompound (XIII) having much higher optical rotation.

The second precursor required for the synthesis of the above compoundsof the formulas (I) and (II) is 3R,4R-4-acetoxy-3-[1R-1-(silyl protectedhydroxy)ethyl]-2-azetidinone, of the formula ##STR26## where R⁶ is aconventional silyl hydroxy protecting group (preferablydimethyl-t-butylsilyl), a compound which is efficiently prepared from6-aminopenicillanic acid, e.g., by the method of Leanza et al.,Tetrahedron, vol. 39, pp. 2505-2513 (1983). Thus, in the next stage ofthe synthesis, the azetidinone (XVI) is converted to the diastereomericcompound of the formula (V) or (VI) wherein R⁶ is hydrogen, by reactionwith the trithiocarbonate (VIIa) or (VIIIa), respectively. With orwithout isolation of said trithiocarbonate, the reactants are combinedin a reaction-inert solvent, such as a (C₁ -C₃)alkanol, e.g.,isopropanol, conveniently in the same solvent as that used forpreparation of the trithiocarbonate, in the presence of excess carbondisulfide (which can be already present in situ from the precedingstep). The reaction is generally carried out at reduced temperature,e.g., ±20° C., conveniently at ice bath temperature (0°-5° C.).

The compound of the formula (V) (VI) wherein R⁷ is hydrogen is thenreacted with an acid fluoride of the formula ##STR27## wherein R¹⁰ is asdefined above, to form the corresponding compound (V) or (VI) wherein R⁷is --COCOOR¹⁰. This step is carried out in a reaction-inert solvent at0° to -80° C. in the presence of a tertiary amine. Lower temperatures,e.g., -30° to -70° C., are preferred. A preferred reaction-inert solventis methylene chloride. A preferred tertiary amine isN,N-diisopropylethylamine.

In the next step of the synthesis, the penem compound of the formula(III) or (IV) wherein R⁴ is a silyl-protecting group and R⁵ correspondsto R¹⁰, is formed by the action of a trialkyl phosphite (e.g., triethylphosphite) on a compound of the formula (V) or (VI) wherein R⁷ is--COCOOR¹⁰. This step is also carried out in a reaction-inert solvent(e.g., ethanol-free chloroform). Temperature is not critical, but willgenerally be above ambient, e.g., 40° to 80° C., conveniently refluxtemperature when chloroform is the solvent.

In the final or penultimate step, the silyl-protecting group is removedby standard methods, e.g., in the case of the dimethyl-t-butylsilyl, bythe action of acetic acid and tetrabutylammonium fluoride in anhydroustetrahydrofuran, to form the compound of the formula (I) or (II) in theform of its pivaloyloxymethyl ester or of the formula (III) or (IV)wherein R⁴ is hydrogen and R⁵ is --CH₂ --CX═CH₂.

Finally, when R⁵ is allyl or 2-chloroallyl, the ester is hydrolyzed toproduce the desired penem of the formula (I) or (II), above, in the formof the acid or its pharmaceutically-acceptable cationic salt. Anhydrousconditions are generally employed to avoid any possible degradation ofthe beta-lactam. Preferred conditions employ 1 to 1.1 molar equivalentsof an alkali metal salt of a lipophilic carboxylic acid (e.g., sodium2-ethylhexanoate) in an anhydrous reaction-inert solvent (e.g.,methylene chloride and/or ethyl acetate) in the presence of catalyticamounts of triphenylphosphine and tetrakis(triphenylphosphine)palladium(e.g., about 0.15 molar equivalents of the former and about 0.075 molarequivalents of the latter). Although temperature is not critical, thereaction is conveniently carried out at ambient temperature. With thesereagents, the compound of the formula (I) or (II) is usually initiallyisolated in the form of its alkali metal (e.g., sodium) salt. Ifdesired, the salt is converted to the free acid form, during or afterisolation, by standard methods, e.g., acidification of an aqueoussolution of the salt, with extraction of the free acid into a waterimmiscible organic solvent.

Other pharmaceutically-acceptable cationic salts of the presentinvention are also readily prepared by standard methods. For example, anequivalent of the corresponding cationic hydroxide, carbonate orbicarbonate or of an amine, is combined with the carboxylic acid in anorganic or aqueous solvent, preferably at reduced temperature (e.g.,0°-5° C.), with vigorous agitation and slow addition of the base. Thesalt is isolated by concentration and/or the addition of a non-solvent.

The compounds of the formula (I) or (II) wherein R represents an in vivohydrolyzable ester are also prepared from the corresponding free acidsor cationic salts according to known methods, readily identified bythose skilled in the penicillin art (see for example, U.S. Pat. Nos.3,951,954; 4,234,579; 4,287,181; 4,342,693; 4,452,796; 4,342,693;4,348,264; 4,416,891; and 4,457,924). In the present instance, thepreferred precursors are hydroxy protected compounds of the formula(III) or (IV) wherein R⁴ is a silyl protecting group, preferablydimethyl-t-butylsilyl, and R⁵ is hydrogen or a salt, preferably thetetrabutylammonium salt. These precursors are obtained by selectivehydrolysis of the corresponding allyl or 2-chloroallyl esters by thespecial method described above. The resulting alkali metal salt ispreferably converted to the tetrabutylammonium salt prior to reactingwith the ester forming reagent, e.g., chloromethyl pivalate or1-chloroethyl ethyl carbonate. Preferred methods of ester formation areexemplified below. The silyl protecting group in the intermediatecompounds is then removed to produce the desired compounds of theformula (I) or (II) wherein R is a radical forming an in vivohydrolyzable ester.

The required acid fluorides (XVII) are prepared from the correspondingacid chlorides using reagents previously used for this purpose, eitheranhydrous cesium fluoride (usually at or near ambient temperature, withreagents initially combined at lower temperature, e.g., 0° to -30° C.),or potassium fluorosulfinate (FSO₂ K, usually at warmer temperatures,e.g., 45°-85° C.). The latter reagent and conditions are preferred whenR⁵ is pivaloyloxymethyl.

Concerning other starting materials required for the process of thepresent invention,3R,4R-4-acetoxy-3-[1R-1-(silyloxy)ethyl]-2-azetidinones are readilyavailable according to the method of Leanza et al., cited above; allyloxalochloride is available according to the method of Afonso et al., J.Am. Chem. Soc., vol. 104, pp. 6138-6139 (1982); 2-chloroallyloxalochloride is available from 2-chloroallyl alcohol and oxalylchloride according to the method detailed below; and pivaloyloxymethyloxalochloride is prepared by a series of steps from benzyl half ester ofoxalic acid and chloromethyl pivalate, also detailed below.

The pure diastereomeric, antibacterial compounds of the formulas (I) and(II) are tested, formulated and used according to methods detailed inabove cited Hamanaka, U.S. Pat. No. 4,619,924, hereby incorporated byreference. Within the human dosage ranges there disclosed, the morepreferred dosage range for the present compounds (I) and (II) is 10-80mg/kg/day both orally and parenterally. These figures are illustrativeonly, since in some circumstances the attending physician will find itmore beneficial to employ dosages outside of these ranges. In vivohydrolyzable esters, particularly the pivaloyloxymethyl and1-(ethoxycarbonyloxy)-ethyl esters, are preferred in oral use, while thesodium or potassium salts are particularly preferred for parenteral use.

The following examples are given by way of illustration are not to beconstrued as limitations of this invention, many variations of which arepossible within the scope and spirit thereof.

EXAMPLE 1 (R)-3-Hydroxythiolane (XI)

In a dry flask under N₂, 19.62 g (0.118 mol) of(R-(2-methanesulfonyloxyethyl)oxirane was dissolved in 600 mlacetonitrile and 100 ml water. Sodium sulfide (18.67 g, 0.239 mol) wasadded and the reaction mixture stirred at room temperature for 24 hours.The two layers were separated and the aqueous layer extracted withmethylene chloride (3×15 ml). The combined organic layers were washedwith 1N sodium hydroxide. The aqueous layer was extracted with methylenechloride (3×150 ml), salted with NaCl, and extracted with an additional2×100 ml of CH₂ Cl₂. All organic layers were combined, washed with 50 ml1N NaOH, 50 ml of saturated NaCl, dried (MgSO₄) and stripped to yieldtitle product, 11.05 g (90% step yield, 90% over-all yield from theS-2-bromo-1,4-butanediol); [alpha]_(D) =+13.93° (c=1.4, CHCl₃);pnmr(CDCl₃)delta(ppm): 1.70-1.90 (b 1H, m, CH), 2.00-2.18 (2H, m, CH,OH), 2.70-2.98 (4H, m, CH₂ S), 4.50-4.52 (1H, m, CHO). For thecorresponding S-isomer, Brown et al., J. Am. Chem. Soc., vol. 108, p.2049 (1986) reported [alpha]_(D) ²⁵ =-14.5 (c=1, CHCl₃).

EXAMPLE 2 (R)-3-(p-Toluenesulfonyloxy)thiolane (Xa, R⁸ =p-tolyl)

In a flame-dried flask under nitrogen, 11.03 g (0.106 mol)(R)-3-hydroxythiolane was dissolved in 150 ml dry methylene chloride andcooled to -5° C. To this was added 25.88 g (0.212 mol)4-dimethylaminopyridine and 20.19 g (0.106 mol)p-toluenesulfonylchloride and the mixture stirred at room temperaturefor 60 hours. It was then washed with 1N hydrochloric acid (25 ml), thewash extracted with methylene chloride (3×50 ml), the combined organiclayers washed with brine, dried (MgSO₄) and evaporated to dryness toprovide 34.73 g crude product. This was filtered through a silica gelpad (5 inch diameter, 4 inches deep), eluting with 1:5 ethylacetate:hexane, then ethyl acetate alone. The product-containingfractions were combined and evaporated to yield 21.52 g (79%) purifiedproduct; [alpha]_(D) =+16.76° (c=2.98, CHCl₃); pnmr(CDCl₃)delta(ppm):1.76-1.90 (1H, m, CH), 2.12-2.26 (b 1H, m, CH), 2.40 (3H, s, CH₃),2.70-3.00 (4H, m, CH₂ S), 5.13-5.16 (1H, m, CHO), 7.25 (2H, d, CH), 7.74(2H, d, CH).

EXAMPLE 3 3R-(p-Toluenesulfonyloxy)thiolane 1R-Oxide (Xb, R⁸ =tolyl)

A solution of 46.30 g (0.179 mol) 3R-(toluene-sulfonyloxy)thiolane in600 ml acetone, under nitrogen was cooled to 0° C. In a separate flask61.73 g (0.100 mol) potassium peroxymonosulfate (2 KHSO₅.KHSO₄. K₂ SO₄;) was stirred in 500 ml distilled water until clear. This was added tothe acetone solution at 0° C. and the mixture allowed to warm to roomtemperature. After 25 minutes 75 ml of 10% (w/v) aqueous sodium sulfitewas added, the acetone was evaporated, 300 ml ethyl acetate added andthe aqueous layer was extracted with ethyl acetate (3×100 ml). Thecombined extracts were dried (MgSO₄) and concentrated to dryness toyield 48.57 g of crude product. The latter was purified by silica gelchromatography using 10:10:1 ethyl acetate:CH₂ Cl₂ :CH₃ OH as eluant toafford purified title product, 34.67 g (71%); [alpha]_(D) =+4.26°(c=3.0, CHCl₃)

EXAMPLE 4 3S-(Acetylthio)thiolane 1R-Oxide (VIIIb)

In a flame-dried flask under nitrogen, 31.67 g (0.1156 mol)3R-(p-toluenesulfonyloxy)thiolane 1R-oxide was dissolved in 300 mlacetone and 19.81 g (0.1734 mol) potassium thioacetate was added. Themixture was heated at reflux for 3.5 hours and allowed to stir at roomtemperature overnight. The mixture was filtered, rinsed and washed with500 ml acetone and the filtrate and washings were evaporated in vacuo toobtain 23.96 g of the desired product as an oil. The oil was purified byflash chromatography on a 120 mm×25 cm silica gel column eluting with19:1 ethyl acetate:methanol collecting 125 ml fractions. Fractions 42-64were combined and stripped to yield purified title product as an oilwhich crystallized on standing, 16.46 g; (80%); m.p. 51°-52° C.;[alpha]_(D) =-83.41° (c=0.86, CHCl₃).

Analysis calculated for C₆ H₁₀ S₂ O₂ : C, 40.4; H. 5.6%. Found: C,40.15; H, 5.53%.

EXAMPLE 5 Sodium 3S-(Thio(thiocarbonyl)thio)thiolane 1R-Oxide (VIIIa,M.sup.⊕ =N.sup.⊕)

In a flame-dried flask under nitrogen, a solution of 1.78 g (10 mmol)3S-(acetylthio)thiolane 1R-oxide in 6 ml ethanol was cooled to -5° C.Sodium ethoxide (21% by weight in ethanol, 3.73 ml, 10 mmol) was addedand the mixture stirred at -5° C. for 30 minutes, then cooled to -20°C., 3.0 ml (50 mmol) carbon disulfide added and stirring continued for30 minutes. To this was added 75 ml anhydrous tetrahydrofuran. Theresulting mixture was stirred for a few minutes, seeded with crystals ofthe title compound, cooled and held at 15° C., and stirred untilcrystallization was complete. The mixture was filtered, washed with coldtetrahydrofuran and then with ethyl ether. The resulting crystals wereair-dried under nitrogen to afford 2.10 g of title product, solvatedwith 0.5 molar equivalents of tetrahydrofuran. Another 592 mg wasrecovered by reworking the mother liquor; m.p. 120°-121° C. (dec.),blackens at 155°-156° C.; [alpha]_(D) =-79.52° (c=0.05, in H₂ O).

EXAMPLE 63S,4R-3-[1R-1-(Dimethyl-t-butylsilyloxy)ethyl]-4-[1R-oxo-3S-thiolanylthio(thiocarbonyl)thio]-2-azetidinone(VI, R⁷ =H, R⁶ =Me₂ tBuSi

In a flame-dried flask under N₂, a solution of3R,4R-4-acetoxy-3-[1R-(dimethyl-t-butylsilyloxy)ethyl]-2-azetidinone[1.87 g, 6.5 mmol; Leanza et al., Tetrahedron 39, pp. 2505-2513 (1983)]in 20 ml isopropyl alcohol and CS₂ (0.15 ml, 2.5 mmol) were combined andcooled to 3° C. The product of the preceding Example (1.36 g, 5 mmol)was added portionwise, maintaining 3° C. After 0.5 hour at 3° C., thereaction was quenched with 40 ml saturated ammonium chloride solution,and then 50 ml ethyl acetate was added. The organic layer was separatedand the aqueous layer was extracted with an additional 2×25 ml ethylacetate. The combined ethyl acetate layers were washed 2×20 ml H₂ O and2×20 ml 20% CaCl₂, dried over MgSO₄, filtered and concentrated in vacuoto yield crude title product, 3.04 g. The latter was dissolved in about2 ml acetone, isopropyl ether was added dropwise until precipitation ofsolid started, the mixture was stirred for one hour, then 120 mlpetroleum ether was added rapidly with stirring. The resulting solid wascollected by filtration, air-dried, then dried in vacuo, and finallychromatographed on silica gel using 19:1 ethyl acetate:methanol aseluant to yield 1.35 g (61%) of purified title product.Recrystallization from 4 ml acetone by the same procedure gave back 1.15g of product; [alpha]_(D) =+109.36° (c=0.20, CHCl₃);pnmr(CDCl₃)(delta)(ppm) 300 MHz: 0.05 (s, 3H), 0.86 (s, 9H), 1.18 (s,3H), 1.74 (s, 2H), 2.68 (m, 3H), 2.82 (m, 1H), 3.17 (m, 2H), 3.74 (q, b1H), 4.25 (t, 1H), 4.52 (t, 1H), 5.61 (s, 1H), 6.52 (s, 1H), 7.20 (s,1H).

EXAMPLE 73S,4R-N-[(2-Chloroallyloxy)oxalyl]-3-[1R-(dimethyl-t-butylsilyloxy)ethyl]-4-[1R-oxo-3S-thiolanylthio(thiocarbonyl)thio]-2-azetidinone

(VI, R⁶ =Me₂ tBuSi, R⁷ =COCOOCH₂ CClCH₂)

A flame-dried, three-neck flask equipped with a dropping funnel and lowtemperature thermometer under a N₂ atmosphere was charged with theproduct of the preceding Example (878 mg, 2 mmol) and 15 ml drymethylene chloride (passed through neutral alumina). The reaction wascooled to -50° to -55° C. internal temperature andN,N-diisopropylethylamine (0.45 ml, 2.6 mmol) was added, keeping thetemperature less than 50° C. Then 2chloroallyl oxalofluoride (0.34 ml,2.6 mmol) was added as fast as possible, again keeping the temperaturebelow 50° C., and the reaction stirred an additional 50 minutes at -50°to -55° C. The reaction was quenched with 15 ml H₂ O, allowed to warm to0° C. and diluted with 20 ml fresh CH₂ Cl₂. The organic layer wasseparated, washed 1×15 ml H₂ O, 1×20 ml pH 7 buffer and 1×25 mlsaturated NaCl, dried over MgSO₄, filtered and concentrated in vacuo toyield 1.05 g of title product as a yellow foam, all of which was useddirectly in the next step.

EXAMPLE 8 2-Chloroallyl5R,6S-6-[1R-(Dimethyl-t-butylsilyloxy)ethyl]-2-(1R-oxo-3S-thiolanylthio)-2-penem-3-carboxylate

(IV, R⁴ =Me₂ tBuSi, R⁵ =CH₂ CClCH₂)

A flame-dried, three-neck flask equipped with a condenser and anequilibrating addition funnel under a N₂ atmosphere was charged with theproduct of the preceding Example (1.05 g, 2 mmol) and 80 ml ethanol-freechloroform. The reaction was heated to a gentle reflux and triethylphosphite (0.74 ml, 48 mmol) in 10 ml ethanol-free chloroform was addeddropwise over a ten-hour period. The reaction was heated at a gentlereflux for an additional ten hours. The reaction was cooled to roomtemperature and concentrated in vacuo. The residue was dissolved in 5 mlethyl acetate. Isopropyl ether (40 ml) was added dropwise with stirringas crystallization began. Finally, 40 ml petroleum ether was addeddropwise, the mixture filtered and solids dried to yield 0.47 g (44%) ofthe product; m.p. 140°-141° C.; [alpha]_(D) =+36.78° (c =0.5, CHCl₃).

EXAMPLE 9 2-Chloroallyl5R,6S-6-(1R-Hydroxyethyl)-2-(1R-oxo-3S-thiolanylthio)-2-penem-3-carboxylate(IV, R⁴ =H, R⁵ =CH₂ CClCH₂)

A flame-dried, three-neck flask equipped with a thermometer and twoaddition funnels under a N₂ atmosphere was charged with the product ofthe preceding Example (0.25 g, 0.46 mmol) and 0.5 ml drytetrahydrofuran. To the stirred reaction was added glacial acetic acid(0.26 ml, 4.6 mmol), followed by tetrabutyl ammonium fluoride intetrahydrofuran (1M, 1.38 ml). The resulting solution was stirredsixteen hours at room temperature, diluted with 15 ml ethyl acetate and4 ml water, adjusted to pH 6.4 with potassium acetate, the layersseparated, and the organic layer washed 3×3 ml water. The latter werecombined and back-washed 3×3 ml CH₂ Cl₂. The combined organic layers(ethyl acetate and CH₂ Cl₂) were dried over Na₂ SO₄, filtered andconcentrated in vacuo to yield crude product, 0.46 g. The crude wastaken up in 25 ml ethyl acetate and washed 3×6 ml H₂ O. The organiclayer was dried over Na₂ SO₄, filtered and stripped to yield purifiedtitle product, 88 mg; m.p. 177°-178° C.; [alpha]_(D) =+45.28° (c=0.25 indimethylsulfoxide).

EXAMPLE 10 Sodium5R,6S-6-(1R-Hydroxyethyl)-2-(1R-oxo-3S-thiolanylthio)-2-penem-3-carboxylate(II, R=Na)

A flame-dried flask wrapped in aluminum foil, under N₂, was charged withthe product of the preceding Example (3.60 g, 8.5 mmol) in 115 ml ofdegassed CH₂ Cl₂, followed by triphenylphosphine (0.72 g, 2.75 mmol),sodium 2-ethylhexanoate (6.72 ml of 1.39M in ethyl acetate, 9.34 mmol)and tetrakis(triphenylphosphine)palladium (0.72 g, 0.62 mmol). Thereaction was stirred at room temperature for fifty minutes, anadditional 72 mg each of triphenylphosphine andtetrakis(triphenylphosphine)palladium were added and the reactionstirred at room temperature an additional twenty minutes. Hplc purityethyl acetate (150 ml) was added to the reaction over a fifteen minuteperiod. The reaction was filtered and the solids air-dried to yieldcrude product, 4.07 g. The latter was slurried with 45 ml ethyl acetatefor 45 minutes, filtered and dried to afford 3.96 g of still crudeproduct. The latter was taken up in 70 ml of water, treated withactivated carbon, filtered and the filtrate freeze-dried to yield titleproduct, 2.63 g.

By the same method, the product of Example 27 below, is converted to thesame title product in similar yield.

EXAMPLE 115R,6S-6-(1R-1-Hydroxyethyl)-2-(1R-oxo-3S-thiolanylthio)-2-penem-3-carboxylicAcid (II, R=H)

The sodium salt of the preceding Example (2.63 g) was dissolved in 8 mlH₂ O and cooled to 0°-5° C. The pH was adjusted to 2.45 with 1N HCl asproduct began to crystallize. The mixture was stirred at 0°-5° C. forforty-five minutes, filtered, washed with a small amount of H₂ O anddried to yield 2.16 g of title product as a white solid; m.p. 135° C.(dec.); [alpha]_(D) =+366.01° (c=1 in dimethylsulfoxide).

EXAMPLE 12 Sterile Sodium5R,6S-6-(1R-Hydroxyethyl)-2-(1R-oxo-3S-thiolanylthio)-2-penem-3-carboxylate(II, R=Na)

The product of the preceding Example (1.95 g) was suspended in 60 ml H₂O and cooled to 0°-5° C. Maintaining that temperature range and usingvigorous stirring, the pH was adjusted from 2.98 to a constant pH of6.00 by the dropwise addition of NaOH (4.2 ml of b 1N, followed by 10.75ml of 0.1N). The solution was millipore filtered into a sterile flaskand freeze-dried (if desired, freeze-dried after subdivision to obtainthe desired dosage in rubber-stoppered sterile vials) to yield steriletitle product, 1.926 g, which, if not already subdivided, can besubdivided into vials at the desired dosage level. This purified productshows m.p. 158° C. (dec.); [alpha]_(D) =+81.31° (c=1 in H₂ O).

For parenteral dosage, the sterile sodium salt is dissolved in sterilewater for injection.

EXAMPLE 13 Tetrabutylammonium5R,6S-6-[1R-(Dimethyl-t-butylsilyloxy)ethyl]-2-(1R-oxo-3S-thiolanylthio)-2-penem-3-carboxylate(IV, R⁴ =Me₂ tBuSi, R⁵ =TBA salt

The product of Example 8 (0.80 g, 1.5 mmol) was reacted according toExample 10 to form intermediate sodium salt in situ. The reactionmixture was diluted with 35 ml ethyl acetate and 4 ml ether, washed 3×10ml H₂ O, the organic layer further diluted with 35 ml hexane, andfinally washed 3×20 ml H₂ O. The six aqueous layers were combined, thenfurther combined with tetrabutylammonium hydrogen sulfate (0.51 g, 1.5mmol) and NaHCO₃ (0.25 g, 3 mmol) in 5 ml H₂ O. After stirring for 15minutes and salting with Na₂ SO₄, the desired product was extracted intoCH₂ Cl₂ (3×90 ml), dried (Na₂ SO₄), treated with activated carbon,filtered and concentrated in vacuo to yield title product, 0.80 g;pnmr(CDCl₃)delta(ppm) 300 MHz: 0.05 (s, 6H), 0.85 (s, 9H), 0.99 (t,12H), 1.28 (d, 3H), 1.30-1.50 (m, 8H), 1.50-1.70 (m, 8H), 2.50-2.82 (m,4H), 2.96-3.10 (m, b 1H), 3.05-3.42 (t, 8H), 3.45-3.62 (m, 2H),3.80-3.92 (m, 1H), 4.05-4.18 (m, 1H), 5.42 (s, 1H).

EXAMPLE 14 Pivaloyloxymethyl5R,6S-6-[1R-(Dimethyl-t-butylsilyloxy)ethyl]-2-(1R-oxo-3S-thiolanylthio)-2-penem-3-carboxylate(IV, R⁴ =Me₂ tBuSi, R⁵ =CH₂ --O--CO--C(CH₃)₃

In flame-dried glassware, under N₂ the product of the preceding Example(0.80 g, 1.13 mmol) was dissolved in 11 ml acetone. Chloromethylpivalate (0.25 ml, 1.71 mmol) was added and the mixture stirred 16 hoursat room temperature, then stripped in vacuo, finally under high vacuum,to yield title product, 1.05 g; pnmr (CDCl₃)delta(ppm) 300 MHz: 0.05 (s,6H), 0.88 (s, 9H), 1.20 (s, 9H), 1.24 (d, 3H), 2.4-2.6 (m, 4H),3.05-3.12 (m, b 1H), 3.6-3.90 (m, 3H), 4.15-4.28 (m, b 1H), 5.59 (s,1H), 5.81 (q, 2H, J_(AB) =12.5 Hz).

The corresponding 1-(ethoxycarbonyloxy)ethyl ester is prepared by thesame method, substituting equivalent 1-chloroethyl ethyl carbonate forchloromethyl pivalate.

Title product is alternatively prepared stepwise by the methods ofExamples 7-9, substituting equivalent pivaloyloxymethyl oxalofluoridefor 2-chloroallyl oxalofluoride in Example 7.

EXAMPLE 15 Pivaloyloxymethyl5R,6S-6-(1R-hydroxyethyl-2-(1R-oxo-3S-thiolanylthio)-2-penem-3-carboxylate(II, R=CH₂ --O--CO--C(CH₃)₃

By the method of Example 9, the product of the preceding Example (0.40g, 0.69 mmol) was converted to present title product. To isolate, thereaction mixture was diluted with 45 ml ethyl acetate and washed 4×9 mlH₂ O. The water washes were combined and back extracted 3×9 ml ethylacetate. All organic layers were combined, washed 2×9 ml saturated NaCl,dried, filtered and concentrated in vacuo, ultimately under high vacuumto yield crude product, 0.28 g. The latter was flash chromatographed ona 40 mm×25 cm column of silica gel, initially eluting with 1:9 ethylacetate:tetrahydrofuran (50 ml fractions 1-10), and then withtetrahydrofuran for subsequent 50 ml fractions. Fractions 18-44 werecombined, evaporated to dryness, and the residue stirred with 70 mlethyl acetate and filtered to yield purified title product, 0.193 g;pnmr(CDCl₃)delta(ppm) 300 MHz: 1.18 (s, 9H), 1.29 (d, 3H, J= 6.3 Hz),2.12 (bs, 1H), 2.6-2.9 (m, 4 Hz), 3.1-3.2 (m, 1H), 3.6-3.90 (m, 3H),4.20-4.32 (m, 1H), 5.64 (s, 1H), 5.76 (q, 2H, J_(AB) =12.5 Hz).

By the same method, the corresponding 1-(methoxycarbonyloxy)ethyl esterof the preceding Example is converted to 1-(ethoxycarbonyloxy)ethyl5R,6S-6-(1R-hydroxyethyl)-2-(1R-oxo-3S-thiolanylthio)-2-penemcarboxylate.

EXAMPLE 16 (S)-3-Bromothiolane (IXa)

To a solution of 97.1 g (0.37 mol)(S)-2-bromo-1,4-di(methanesulfonyloxy)butane in 1400 ml methanol wasadded over 1 hour a solution of 98.23 g (0.41 mol) sodium sulfidenonahydrate in 500 ml water at 19°-26° C. The mixture was stirred atroom temperature for 80 hours. The reaction mixture was diluted with 6liters methylene chloride, the organic layer separated, washed 2×1 literH₂ O, 1×1500 ml brine, dried (Na₂ SO₄) and the solvent evaporated toprovide 36.5 to 46.8 g (59-68%) of crude product as a pale yellow oil.The latter was distilled in vacuo to yield a mobile water clear liquidproduct, b.p. 32° (0.4 ml), 26.0 g (38% over-all). Alternatively, thecrude product (3 g) was flash chromatographed on an 80 mm×15 cm silicagel column using 9:1 hexane:ethyl acetate as eluant, collecting 100 mlfractions. Evaporation of fractions 14 and 15 gave purified titleproduct as an oil, 2.03 g (39% over-all); [alpha]_(D) =-104.57° (c=0.53in CHCl₃).

EXAMPLE 17 3S-Bromothiolane 1-S-Oxide (IXb)

By the method of Example 3, 29.3 g (0.175 mol) (S)-3-bromothiolane wasconverted to present title product as a white solid (88%). If desired,the product (10.1 g) was further purified by flash chromatography on a90 mm×15 cm silica gel column eluting with ethyl acetate in 100 mlfractions. Fractions 36-64 were stripped to yield 4.73 g of purifiedtitle product; m.p. 68°-70° C.; [alpha]_(D) =-99.94° (c=5 in CHCl₃).

Analysis calculated for C₄ H₇ OBrS: C, 26.64; H, 3.86; S, 17.52%. Found:C, 26.47; H, 3.89; S, 17.71%.

EXAMPLE 18 3R-(Acetylthio)thiolane 1S-Oxide

By the method of Example 4, the product of the preceding Example (24 g)was converted to crude title product which crystallized on pumping underhigh vacuum, 26 g. The latter was purified by flash chromatography on a500 mm×24 cm silica gel column using 49:1 ethyl acetate:methanol aseluant collecting 125 ml fractions. Fractions 50-90 were combined andstripped to yield purified title product, 19.6 g (85%); m.p. 54°-56° C.;[alpha]_(D) =+85.73° (c=1 in CHCl₃). A sample was recrystallized fromisopropyl ether; m.p. 57°-59° C.

Analysis calculated for C₆ H₁₀ O₂ S₂ : C, 40.42; H, 5.65%. Found: C,40.69; H, 5.45%.

EXAMPLE 193S,4R-3-[1R-(Dimethyl-t-butylsilyloxy)ethyl]-4-1S-oxo-3R-thiolanylthio(thiocarbonylthio)-2-azetidinone(V, R⁷ =H, R⁶ =Me₂ tBuSi)

Sodium metal (2.23 g, 0.097 mol) was suspended in 340 ml dry isopropylalcohol and refluxed 2.5 hours to produce a clear solution of sodiumisopropoxide, then cooled to room temperature. Meanwhile, under nitrogenin a flame-dried flask, the product of the preceding Example (18.1 g,0.102 mol) was dissolved in 260 ml dry isopropyl alcohol and cooled to0° C. With stirring the sodium isopropoxide solution was added over 17minutes; maintaining 0°-2° C. After stirring for an additional 30minutes at 0° C., the mixture was chilled to -30° C. and carbondisulfide (23.3 g, 18.4 ml, 0.306 mol) in 50 ml isopropyl alcohol addeddropwise. The resulting yellow suspension was warmed to 0° C. andstirred an additional 10 minutes, thus producing sodium3R-(thio(thiocarbonyl)thio)thiolane 1S-oxide.

To the latter suspension was added dropwise a solution of3R,4R-4-acetoxy-3-[1R-(dimethyl-t-butylsilyloxy)ethyl]-2-azetidinone(32.1 g, 0.112 mol), maintaining 0°-3° C. After stirring at 0°-2° C. anadditional 20 minutes, the reaction mixture was poured into 900 mlsaturated NH₄ Cl and 900 ml ethyl acetate, and diluted with anadditional 2,250 ml of ethyl acetate. The organic layer was separated,washed sequentially with 1×900 ml H₂ O, 1×900 ml 20% CaCl₂, 1×900 ml H₂O, 1×900 ml 20% CaCl₂ and 2×900 ml saturated NaCl, dried (Na₂ SO₄),filtered and stripped in vacuo to solids, which were dried by repeatedaddition of 1:1 ethyl acetate:hexane and stripping. The solid residuewas repulped in 300 ml hexane and title product recovered by filtration,37.0 g. The latter was twice recrystallized by dissolving in 50-60 ml ofacetone, with crystallization induced by the slow addition, withstirring, of 500 ml of isopropyl ether to yield purified title product26.4 g; m.p. 90°-94° (dec.); [alpha]_(D) =+315.05° (c=1 in CHCl₃);ir(KBr) 1766 cm⁻¹.

EXAMPLE 203S,4R-N-[(2-Chloroallyloxy)oxalyl]-3-[1R-(dimethyl-t-butylsilyloxy)ethyl]-4-[1S-oxo-3R-thiolanylthio(thiocarbonyl)thio]-2-azetidinone(V, R⁶ =Me₂ tBuSi, R⁷ =COCOCH₂ CClCH₂)

A flame-dried, three-neck flask equipped with a dropping funnel and lowtemperature thermometer under a N₂ atmosphere was charged with theproduct of the preceding Example (26.4 g, 60 mmol) and 300 ml drymethylene chloride (passed through neutral alumina). The reaction wascooled to -60° C. internal temperature and N,N-diisopropylethylamine(13.6 ml, 78 mmol) was added via syringe followed by 2-chloroallyloxalofluoride (13.0 g, 78 mmol), which was added dropwise maintaining-60° to -55° C. The reaction was then stirred at -50° to -55° C. for 50minutes, quenched with 100 ml H₂ O, warmed to 0° C. and diluted with anadditional 100 ml H₂ O. The organic layer was separated, washed with anadditional 2×200 ml H₂ O, 2×200 ml pH 7 buffer and 200 ml brine, driedover Na₂ SO₄, filtered and concentrated in vacuo to yield title product,33.2 g of a yellow foam, which was used directly in the next step.

EXAMPLE 21 2-Chloroallyl5R,6S-6-[1R-(Dimethyl-t-butylsilyloxy)ethyl]-2-(b1S-oxo-3R-thiolanylthio)-2-penem-3-carboxylate (III, R⁴ =Me₂ tBuSi, R⁵=CH₂ CClCH₂)

By the method of Example 8, the entire batch of crude product from thepreceding Example (33.2 g, 0.060 mol assumed) was converted to presenttitle product, crystallized from ethyl acetate/diisopropyl ether in likemanner to yield 11.3 g. The latter was further purified by repulping in200 ml diisopropyl ether to yield 9.8 g; m.p. 122°-125° C. (dec.);ir(KBr) 1784 cm⁻¹ ; [alpha]_(D) =+158.13° (c=1 in CHCl₃).

EXAMPLE 22 2-Chloroallyl5R,6S-6-(1R-Hydroxyethyl)-2-(1S-oxo-3R-thiolanylthio)-2-penem-3-carboxylate(III, R⁴ =H, R⁵ =CH₂ CClCH₂)

By the method of Example 9, the product of the preceding Example (6.0 g,11.2 mmol) was converted to crude title product. The latter was slurriedin 60 ml of ethyl acetate to produce purified title product as a whitesolid, 4.0 g; m.p. 156°-158° C. (dec.); [alpha]_(D) =+186.7° (c=0.35 indimethylsulfoxide).

EXAMPLE 235R,6S-6-(1R-Hydroxyethyl)-2-(1R-oxo-3S-thiolanylthio)-2-penem-3-carboxylicacid (I, R=H)

By the method of Example 10, the product of the preceding Example (4.24g, 10 mmol) was converted to crude sodium salt of title product (4.56g), which was slurried in 50 ml of ethyl acetate for 1 hour to yieldpartially purified sodium salt, 4.36 g. The latter was converted tofreeze-dried sodium salt according to Example 10. The entire batch offreeze-dried sodium salt was redissolved in 11 ml H₂ O, cooled to 0°-5°C. and the pH slowly lowered from 6.9 to 4.0 with 3N HCl.Crystallization was induced by scratching, and the pH was then slowlylowered to 2.5. Title product was recovered by filtration, with repulpin 20 ml of hplc grade ethyl acetate, 2.6 g; m.p. 185°-187° C. (dec.);[alpha]_(D) =+128.67° (c=1 in dimethylsulfoxide).

Sterile sodium salt was prepared according to Example 12 (2.3 g from 2.2g of acid); m.p. 120°-123° C. (gassing); [alpha]_(D) =+115.29° (c=2.1 inH₂ O).

EXAMPLE 24 Tetrabutylammonium5R,6S-6-[1R-(dimethyl-t-butylsilyloxy)ethyl]-2-(1R-oxo-3S-thiolanylthio)-2-penem-3-carboxylate(III, R⁴ =Me₂ tBuSi, R⁵ =TBA Salt)

By the method of Example 10, the product of Example 21 (1.2 g, 2.23 mol)was converted to sodium5R,6S-6-[1R-(dimethyl-t-butylsilyl)ethyl]-2-(1R-oxo-3S-thiolanylthio)-2-penem-3-carboxylatein CH₂ Cl₂. The reaction mixture was diluted with 50 ml ethyl acetate,10 ml ether and 50 ml hexane, then extracted 5×25 ml of H₂ O to yield anaqueous solution of the sodium salt. To the combined aqueous extractswas added a solution of tetrabutylammonium hydrogen sulfate (0.76 g,2.23 mmol) and NaHCO₃ (0.375 g, 4.46 mmol) in 10 ml H₂ O. The solutionwas stirred 20 minutes, then extracted 3×140 ml CH₂ Cl₂, and theextracts combined, dried (Na₂ SO₄), carbon treated, filtered andstripped to yield title product as a foam, 1.29 g; pnmr(CDCl₃)delta(ppm)300 MHz: 0.06 (s, 6H), 0.85 (s, 9H), 0.78 (t, 12H), 1.25 (d, 3H),1.28-1.50 (m, 8H), 1.50-1.70 (m, 8H), 2.40-2.80 (m, 4H), 2.90-3.10 (m,1H), 3.22-3.38 (t, 8H), 3.45-3.55 (m, 2H), 3.90-4.02 (m, 1H), 4.05-4.20(m, 1H), 5.42 (s, 1H).

EXAMPLE 25 Pivaloyloxymethyl5R,6S-6-[1R-(Dimethyl-t-butylsilyloxy)ethyl]-2-(1R-oxo-3S-thiolanylthio)-2-penem-3-carboxylate(III, R⁴ =Me² tBuSi, R⁵ =CH₂ --O--CO--C(CH₃)₃)

By the method of Example 14, the product of the preceding Example (1.29g, 1.8 mmol) was converted to title product, initially isolated as abrownish oil which was flash chromatographed on a 50 mm×25 cm silica gelcolumn eluting with 19:1 ethyl acetate in 50 ml fractions. Fractions14-20 were combined and stripped to yield title product as a solid, 0.64g; pnmr(CDCl₃)delta(ppm) 300 MHz: 0.08 (s, 6H), 0.88 (s, 9H), 6.22 (s,9H), 1.25 (d, 3H), 2.6-2.85 (m, 4H), 3.08-3.20 (m, 1H), 3.60-3.78 (m,2H), 3.90-4.00 (m, 1H), 4.2-4.3 (m, 1H), 5.65 (s, 1H), 5.86 (q, 2H,J_(AB) =2.5 Hz).

EXAMPLE 26 Pivaloyloxymethyl5R,6S-6-(1R-hydroxy-ethyl)-2-(1R-oxo-3S-thiolanylthio)-2-penem-3-carboxylate(I, R=CH₂ --O--CO--C(CH₃)₃)

By the method of Example 9, the product of the preceding Example (0.638g, 1.104 mmol) was converted to crude title product which waschromatographed on a 50 mm×25 cm silica gel column collecting 50 mlfractions; 1:9 ethyl acetate:tetrahydrofuran was the eluant forfractions 1-12, pure tetrahydrofuran for fractions 13-20. The latterfractions were combined, stripped and the solid residue (422 mg)repulped in 15 ml of 2:1 petroleum ether:ethyl acetate and then 22 ml of10:1 petroleum ether:ethyl acetate to yield purified title product,0.314 g; m.p. 162°-164° C. (dec.); [alpha]_(D) =+109.7° (c=0.5 indimethylsulfoxide); pnmr(CDCl₃)delta(ppm) 250 MHz: 1.20 (s, 9H), 1.34(d, 3H, J=6.3 Hz), 2.12 (d, 1H), 2.6-2.9 (m, 4H), 3.06-3.22 (m, 1H),3.60-3.75 (m, 2H), 3.85-3.98 (m, 1H), 4.2-4.35 (m, 1H), 5.68 (s, 1H),5.86 (q, 2H, J_(AB) =12.5 Hz).

EXAMPLE 27 Allyl5R,6S-6-(1R-Hydroxyethyl)-2-1R-oxo-3S-thiolanylthio)-2-penem-3-carboxylate(IV, R⁴ =H, R⁵ =CH₂ CHCH₂

Using the methods of Examples 7-9, substituting equivalent allyloxalofluoride in place of 2-chloroallyl oxalofluoride in Example 7, theproduct of Example 6 is converted to present title product.

PREPARATION 1 2-Chloroallyl Oxalofluoride [(2-Chloroallyloxy)oxalylFluoride] CH₂ ═CClCH₂ O(CO)COF

Under dry N₂ in flame dried glass apparatus, cesium fluoride (167 g, 1.1mol) was placed in a 1 liter single neck flask and placed under highvacuum and gently heated with a flame until the solid became freeflowing, then cooled to room temperature. Acetonitrile, distilled fromCaH₂ (183 ml) was added and the mixture cooled to -20° C. internaltemperature. 2-Chloroallyl oxalochloride (183 g, 1.0 mol) was addeddropwise over a 30 minute period and the mixture slowly warmed to roomtemperature, stirred at that temperature for 16 hours, and byproductcesium chloride recovered by filtration with acetonitrile wash. Thefiltrate and wash were combined and stripped, and the residue distilledat reduced temperature to yield 129 g (77%) of the desired product, b.p.62°-64° C./22 mm.

IR(CHCl₃)cm⁻¹ 1770, 1870.

¹ H-NMR(CDCl₃)delta(ppm) 4.80 (s, 2H), 5.4-5.6 (m, 2H).

PREPARATION 2 Allyl Oxalofluoride [Allyloxalyl Fluoride] CH₂ ═CHCH₂O(CO)COF

By the procedure of the preceding Preparation, allyl oxalochloride(252.5 g, 1.70 mol) and cesium fluoride (284 g, 1.87 mol) were convertedto twice distilled title product, b.p. 48°-50° C./35 mm; 124°-126° C.(atmospheric pressure).

¹ H-NMR(CDCl₃)250 MH₃, delta: 4.76 (d, 2H, J=6 Hz), 5.28 (dd, 1H, J=1, 7Hz), 5.37 (dd, 1H, J=1, 17 Hz), 5.90 (ddt, 1H, J=6, 11, 17 Hz).

¹³ C-NMR(CDCl₃)63 MHz, delta: 68.5 (t), 120.4 (t), 129.7 (d), 146.3 (d,J_(C-F) =375 Hz), 153.0 (d, J_(C-C-F) =87 Hz). IR(neat) 1860 (C═O), 1770(C═O), 1120 cm⁻¹.

PREPARATION 3 2-Chloroallyl Oxalochloride [(2-Chloroallyloxy)oxalylChloride]

Oxalyl chloride (130 ml, 1.49 mol) was placed in a dry 3-neck flaskunder N₂ and cooled to 0° C. With stirring, 2-chloroallyl alcohol (138g, 1.49 mol) was added dropwise in a manner which maintained thetemperature at 0°-2° C. and controlled the vigorous evolution of HCl,then allowed to warm to room temperature and held 16 hours and distilledto yield title product, 214 g, b.p. 82°-84° C./23 mm.

PREPARATION 4 Benzyl Oxalochloride [(Benzyloxy)oxalyl Chloride]

Under N₂, oxalyl chloride (262 ml) was dissolved in 1 liter anhydrousether and heated to reflux, at which temperature benzyl alcohol (207 ml)was added over 70 minutes. After refluxing a further 16 hours, ether wasstripped and the residue distilled at reduced pressure to yield 372 g(94%) of title product, b.p./0.7 mm 85° C.

PREPARATION 5 Oxalic Acid, Half Benzyl Ester

Title product of the preceding Preparation (180 g, 0.91 mol) in 800 mlether was cooled in an acetone-dry ice bath. As the mixture was allowedto warm to 0° C., aqueous NH₄ OH (2M, 906 ml, 0.91 mol) was addedportionwise. The mixture was then warmed to room temperature, stirred 1hour, and the pH adjusted to 8.5 with 95 ml 2M NH₄ OH. The aqueous layerwas separated, extracted 2×400 ml ether, layered with 500 ml freshether, cooled to 10° C. and the pH adjusted to 1.5 with 2M HCl. Thelayers were separated, the aqueous layer extracted 2×400 ml ether, andthe three acidic organic layers combined, washed with 500 ml brine,dried over Na₂ SO₄ and stripped to yield title product as white solids,163 g.

¹ H-NMR(CDCl₃)delta(ppm): 5.2 (s, 1H), 6.95 (s, 2H), 7.3 (s, 5H).

PREPARATION 6 Benzyl Pivaloyloxymethyl Oxalate

The product of the preceding Preparation (163 g, 0.91 mol) was dissolvedin 1 liter CHCl₃ and carefully neutralized (foaming) with NaHCO₃ (76.2g, 0.91 mol). Separately, tetrabutylammonium hydrogen sulfate (308 g,0.91 mol) in 1.5 liters H₂ O was carefully neutralized with a likequantity of NaHCO₃. The former slurry was added slowly to the lattersolution, the mixture stirred vigorously for 20 minutes, the aqueouslayer separated and washed with 500 ml fresh CHCl₃. The organic layerswere combined, dried over Na₂ SO₄ and stripped to yieldtetrabutylammonium benzyl oxalate, 478 g. The latter was taken up in 400ml acetone. Chloromethyl pivalate (118 ml, 0.82 mol) was added and themixture stirred under N₂ for 16 hours at ambient temperature. Theacetone was stripped, and the residue taken up in 1 liter ethyl acetate,washed 4×500 ml H₂ O and 1×500 ml brine, dried over Na₂ SO₄ and strippedto yield title product as an oil, 201 g; tlc Rf 0.60 (2:3 ethylacetate:hexane).

¹ H-NMR(CDCl₃, 90 MHz)delta(ppm): 1.21 (s, 9H), 5.2 (s, 2H), 5.8 (s,2H), 7.3 (s, 5H).

PREPARATION 7 Oxalic Acid, Half Pivaloyloxymethyl Ester

Title product of the preceding Preparation (27.3 g, 0.093 mol) and 2.8 gof 10% Pd/C were combined in 150 ml ethyl acetate and hydrogenated in aPaar hydrogenation apparatus at 4x atmospheric pressure and ambienttemperature for 1.5 hours. The catalyst was recovered by filtration overdiatomaceous earth and the filtrate stripped to yield title product asan oil, 19.3 g.

¹ H-NMR(CDCl₃, 90 MHz)delta(ppm): 1.21 (s, 9H), 5.96 (s, 2H), 10.31 (s,1H).

PREPARATION 8 Pivaloyloxymethyl Oxalochloride

Title product of the preceding Preparation (19.2 g, 0.094 mol) wasdissolved in 20 ml benzene and added portionwise over 20 minutes tooxalyl chloride (47.7 g, 33 ml, 0.376 mol) in 100 ml benzene. After 30minutes, the mixture was stripped and the residue (19.2 g) distilled toyield title product, 16.4 g; b.p. 83° C./0.4 mm.

PREPARATION 9 Pivaloyloxymethyl Oxalofluoride [PivaloyloxymethyloxalylFluoride] (CH₃)₃ C(CO)OCH₂ O(CO)COF

Potassium fluorosulfinate (80% KSO₂ F, 2.40 g, 1.92 g corrected, 0.016mol) was added to oxalyl chloride (3.50 g, 0.016 mol) and the mixturegradually warmed in an oil bath to 60° C., at which point vigorous gasevolution began. The bath was removed. Once the reaction subsided, theoil bath was replaced, the mixture warmed to 80° C. and held for 15minutes, cooled to 60° C. and distilled from a bath at 60° C. to yieldtitle product, 1.19 g; b.p. 52°-54° C./0.4 mm.; solidified on storage at-50° C., melts at ambient temperature.

¹³ C-NMR: 176.6, 152.6 and 151.5, 148.1 and 140.2, 81.7, 38.8, and 26.6,with splitting of oxalate carbonyls 89 Hz and 252.6 Hz.

PREPARATION 10 (S)-2-Bromosuccinic Acid

To a solution of 1,000 g (9.72 mol) sodium bromide in 2.1 liters 6Nsulfuric acid under nitrogen was added 323.1 g (2.43 mol) L-asparticacid and the resulting solution cooled to 5° C. To this was added inportions over 1.5 hours, 201.4 g (2.92 mol) sodium nitrite while keepingthe temperature below 10° C. After the addition was completed, one literof distilled water was added, followed by 73.07 g (1.22 mol) urea. Theresulting mixture was poured into a separatory funnel and extracted with2.5 liters ethyl ether. To the aqueous layer was added 500 g sodiumchloride, and the mixture extracted three times with ether (3×1.25liters). The combined ether layers were washed with brine, dried (Na₂SO₄) and the solvent evaporated in vacuo to yield 303 g (63%) of thedesired compound; [alpha]_(D) =-73.5° (c=0.6 in ethyl acetate); m.p.185° C.

PREPARATION 11 (S)-2-Bromo-1,4-butanediol

Employing flame-dried glassware under nitrogen, 303.14 g (1.54 mol)(S)-2-bromosuccinic acid was dissolved in 3.2 liters anhydroustetrahydrofuran (THF) and the mixture cooled to -20° C. To this wasadded dropwise over 90 minutes, a solution of 350.78 g borane-methylsulfide complex in 438 ml of tetrahydrofuran (4.62 mol). The mixture wasstirred while warming slowly to 18° C. whereupon the reaction mixtureliberated hydrogen gas and became exothermic. The mixture was cooled indry ice/acetone while passing nitrogen over the mixture. After 15minutes the cooling bath was removed, and the reaction allowed to warmto ambient temperature and maintained under a sweep of nitrogen for 60hours. A liter of methanol was added slowly, the sweep of nitrogencontinued for 30 minutes, and the solvents then evaporated. The residuewas taken up in one liter methanol and solvent evaporated again. Thiswas repeated two more times to obtain 282.41 g (100%) of the desireddiol.

PREPARATION 12 (R)-(2-Methanesulfonyloxyethyl)oxirane

A. Employing dry glassware, under nitrogen, 20 g (0.118 mol)(S)-2-bromo-1,4-butanediol was dissolved in 400 ml dry methylenechloride and 69.41 g (0.213 mol) cesium carbonate was added. The mixturewas stirred at room temperature for 40 hours and then filtered with CH₂Cl₂ wash. The combined filtrate and wash liquor was used directly inPart B below. When desired, the solvent was stripped to yieldintermediate (R)-(2-hydroxyethyl)oxirane in virtually quantitativeyield.

B. In a flame-dried flask, under nitrogen, was added the entire productsolution from Part A (about 800 ml), which was then cooled to -25° C.Triethylamine (21.55 g, 0.213 mol) was added followed by slow additionof 20.34 g (0.178 mol) of methanesulfonyl chloride over 25 minutes,maintaining less than -20° C. The resulting mixture was allowed to warmto room temperature over 1.5 hours, extracted 1×50 ml pH 4 buffer, andthe buffer back-extracted 3×50 ml CH₂ Cl₂. The organic extracts werecombined with the original organic layer, extracted 1×50 ml saturatedNaCl, and the brine back-extracted with 3×50 ml CH₂ Cl₂ and the organicextracts combined with the original organic layer, which was stripped toyield title product in substantially quantitative yield; [alpha]_(D)=+34.7° (c=0.1 in CH₂ Cl₂); pnmr(CDCl₃)delta(ppm): 1.76-1.85 (1H, m,CH), 2.02-2.11 (1H, m, CH), 2.50-2.52 (1H, m, CHO), 2.77-2.80 (1H, m,CHO), 2.98-3.04 (1H, m, CHO), 2.99 (3H, s, CH₃), 4.32 (2H, t, CH₂ O).

PREPARATION 13 (S)-2-Bromo-1,4-di(methanesulfonyloxy)butane

A solution of 70 g (0.414 mol) (S)-2-bromo-1,4-butanediol in 1.5 litersmethylene chloride was cooled in ice and 173 ml (1.24 mol) triethylamine(dried over potassium hydroxide) was added to give a clear solution. Tothis was added dropwise over 80 minutes at 5° to 15° C., 96 ml (1.24mol) methanesulfonyl chloride. The mixture was then stirred at roomtemperature for 2.5 hours, washed 2×750 ml with water and 1×750 mlbrine, dried (MgSO₄), and the solvent evaporated to give an amber oilwhich was purified by chromatography on a 140 mm×25 cm silica gelcolumn, eluting with 9:1 chloroform:ethyl acetate. The product fractionswere combined and solvent evaporated to give 105 g (97%) of the titlecompound as a waxy white solid; [alpha]_(D) =-34.49° (c=5 in CHCl₃).

We claim:
 1. A penem having the absolute stereochemical formula ##STR28## wherein R is hydrogen or a radical forming an ester hydrolyzable under physiological conditions; or a pharmaceutically-acceptable cationic salt thereof when R is hydrogen.
 2. The penem of claim 1 wherein R is hydrogen.
 3. A compound of claim 1 wherein R is a radical group forming an ester hydrolyzable under physiological conditions.
 4. A compound of claim 3 wherein R is:(5-methyl-1,3-dioxol-2-on-4-yl)methyl; 1H-isobenzofuran-3-on-1-yl; gamma-butyrolacton-4-yl; --CHR¹ OCOR² ; or --CHR¹ OCOOR³ ; wherein R¹ is hydrogen or methyl; R² is (C₆)alkyl, (C₁ -C₆)carboxyalkyl, carboxycyclohexyl or carboxyphenyl; and R³ is (C₁ -C₆)alkyl.
 5. The compound of claim 4 wherein R is ethoxycarbonyloxy)ethyl.
 6. The compound of claim 4 wherein R is pivaloyloxymethyl.
 7. A pharmaceutical composition comprising an antibacterial amount of a compound of claim
 1. 8. A method of treating a bacterial infection in a mammal which comprises administering to said mammal an antibacterial amount of a compound of claim
 1. 9. A compound having the absolute stereochemical formula ##STR29## wherein R⁴ is hydrogen or a conventional silyl hydroxy protecting group; R⁵ is hydrogen, ##STR30## and X is hydrogen or chloro; with the proviso that R⁵ is --CH₂ --CX═CH₂ when R⁴ is hydrogen; or a salt thereof when R⁵ is hydrogen.
 10. The compound of claim 9 wherein R⁴ is hydrogen, R⁵ is --CH₂ --CX═CH₂, and X is chloro.
 11. The compound of claim 9 wherein R⁴ is dimethyl(t-butyl)silyl, R⁵ is --CH₂ --CX═CH₂, and X is chloro.
 12. The compound of claim 9 wherein R⁴ is dimethyl(t-butyl)silyl and R⁵ is --CH₂ --O--CO--C(CH₃)₃. 